文章：

上皮细胞极性，干细胞与癌症

Epithelial cell polarity, stem cells and cancer

原文发布日期：2011-12-15

DOI: 10.1038/nrc3169

类型: Review Article

开放获取: 否

要点：

1. The proteins that finely control epithelial cell polarity are known as tumour suppressors or proto-oncoproteins. Loss of epithelial cell polarity — through deregulation of these proteins — is crucial for cancer cell invasion and advanced tumour progression. Accumulating evidence indicates that epithelial cell polarity cues and polarized cell divisions causally contribute to restrict carcinoma formation.
2. Cell polarity proteins crosstalk with signalling pathways that regulate cell growth and proliferation, including the WNT and Hippo pathways, and liver kinase B1 (LKB1)–mTOR-dependent energy metabolism.
3. The components of the evolutionarily conserved Hippo pathway function as important tumour suppressors. Recent studies have provided evidence that the cell polarity regulators lethal (2) giant larvae homologue (LGL; also known as LLGL), atypical protein kinase C (aPKC) and crumbs homologue (CRB), and the adherens junctions components E-cadherin–α-catenin or E-cadherin–β-catenin regulate the Hippo pathway in mammalian and Drosophila melanogaster epithelial cells.
4. The LKB1–AMPK–mTOR pathway, which is a molecular link between polarity and the metabolic status of a cell, is essential in the process of tumorigenesis.
5. The maintenance of most adult epithelial tissues relies on the presence of polarized stem cells, which self-renew through symmetric cell divisions. During differentiation stem cells reorient their mitotic spindles and divide asymmetrically in order to generate the specialized cells that drive epithelial function and homeostasis. The genes that control epithelial cell polarity also regulate spindle orientation and the symmetry of cell divisions in stem cells.
6. Epithelial tumours are highly heterogeneous, and the cell-of-origin that can initiate tumorigenesis is an area of extensive study. Two theories of tumour initiation have been postulated; one proposes that some tumours arise from normal adult stem or progenitor cells that have gone awry, and the other postulates that they arise from differentiated cells that acquire self-renewal capabilities. Evidence for the stem or progenitor cell-of-origin model has been provided for some carcinomas or specific subtypes of carcinomas; however, this seems to be unlikely or has not been well defined for several others.

要点翻译：

1. 精细调控上皮细胞极性的蛋白质被称为肿瘤抑制蛋白或原癌蛋白。上皮细胞极性的丧失——通过这些蛋白质的失调——对癌细胞侵袭和晚期肿瘤进展至关重要。越来越多的证据表明，上皮细胞极性信号和极性化细胞分裂对限制癌形成具有因果作用。
2. 细胞极性蛋白与调控细胞生长和增殖的信号通路（包括WNT和Hippo通路）以及肝激酶B1（LKB1）-mTOR依赖的能量代谢存在交互作用。
3. 进化上保守的Hippo通路组分作为重要的肿瘤抑制因子发挥作用。近期研究证实，细胞极性调控因子 lethal (2) giant larvae同源物（LGL）、非典型蛋白激酶C（aPKC）与crumbs同源物（CRB），以及粘附连接组分E-钙黏蛋白–α-连环蛋白或E-钙黏蛋白–β-连环蛋白在哺乳动物和果蝇上皮细胞中调控Hippo通路。
4. LKB1–AMPK–mTOR通路作为细胞极性与代谢状态之间的分子桥梁，在肿瘤发生过程中至关重要。
5. 大多数成体上皮组织的维持依赖于极性化干细胞的存在，这些干细胞通过对称分裂进行自我更新。在分化过程中，干细胞重新定向其纺锤体并进行不对称分裂，以产生驱动上皮功能和稳态的特化细胞。控制上皮细胞极性的基因同时调控干细胞中纺锤体的定向和细胞分裂的对称性。
6. 上皮性肿瘤具有高度异质性，能够启动肿瘤发生的起源细胞是目前广泛研究的领域。现有两种肿瘤发生假说：一种认为某些肿瘤源于失常的正常成体干细胞或祖细胞，另一种则假定它们源于获得自我更新能力的分化细胞。某些癌症或特定癌症亚型已为干细胞或祖细胞起源模型提供证据；然而在其他多种肿瘤中，这一模型似乎不适用或尚未明确。

英文摘要：

After years of extensive scientific discovery much has been learned about the networks that regulate epithelial homeostasis. Loss of expression or functional activity of cell adhesion and cell polarity proteins (including the PAR, crumbs (CRB) and scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. But the key roles of these proteins in crosstalk with the Hippo and liver kinase B1 (LKB1)–AMPK pathways and in epithelial function and proliferation indicate that they may also be associated with the early stages of tumorigenesis. For example, deregulation of adhesion and polarity proteins can cause misoriented cell divisions and increased self-renewal of adult epithelial stem cells. In this Review, we highlight some advances in the understanding of how loss of epithelial cell polarity contributes to tumorigenesis.

摘要翻译： 

经过多年的广泛科学发现，人们对调控上皮稳态的网络已有了深入了解。细胞黏附与细胞极性蛋白（包括PAR、crumbs（CRB）和scribble（SCRIB）复合体）的表达缺失或功能丧失，与肿瘤进展和侵袭的晚期阶段密切相关。然而，这些蛋白在与Hippo及肝激酶B1（LKB1）–AMPK信号通路的交互中，以及在上皮功能与增殖中的关键作用，表明它们也可能与肿瘤发生的早期阶段相关。例如，黏附与极性蛋白的失调可导致细胞分裂方向异常及成体上皮干细胞自我更新增加。在本综述中，我们重点介绍了关于上皮细胞极性缺失如何促进肿瘤发生的研究进展。

原文链接：

Epithelial cell polarity, stem cells and cancer